Kazuo Yoshino

Boron Neutron Capture Therapy of Malignant Melanoma Using 10B-Paraboronophenylalanine with Special Reference to Evaluation of Radiation Dose and Damage to the Normal Skin

A treatment regimen for boron neutron capture therapy of malignant melanomas is described using 10B-paraboronophenylalanine as the tumor-targeting compound. As a therapeutic dose, we adopted the maximum tolerable dose for the skin regardless of tumor 10B concentration. In practice, the maximum neutron fluence should be decided prior to starting irradiation. For this purpose, the kinetics of the concentration of 10B in the blood and skin and the skin-to-blood ratios were analyzed in the six patients who received 170 mg/kg of the compound intravenously, and skin concentrations during irradiation were predicted using a standard skin factor curve. This yields a skin concentration at time T based on the blood concentration at time 0. We calculated the maximum tolerable fluence yielding but not exceeding 18 RBE-Gy by assuming that the RBE of 14N(n,p)14C and 10B(n, alpha)7Li reaction for skin damage is 2.5. Actual skin reactions in three of five patients treated with the therapy were, as predicted, within tolerable limits, and we were able to obtain complete tumor regression in four cases. The results indicate that application of our logical approach will be useful for subsequent cases and further development of this therapy.

A unique in vivo assessment of 4-[10B]borono-L-phenylalanine in tumour tissues for boron neutron capture therapy of malignant melanomas using positron emission tomography and 4-borono-2-[18F]fluoro-L-phenylalanine

A unique in vivo approach to assessing the concentrations of 4-[10B]borono-L-phenylalanine (L-BPA), a melanoma targeting compound for boron neutron capture therapy (BNCT), was investigated using L-BPA labelled with positron-emitting 18F (half-life = 110 min), i.e., 4-[10B]borono-2-[18F]fluoro-L-phenylalanine (L-[18F]FBPA). High melanoma uptake of L-[18F]FBPA was reduced slightly by competition with L-BPA in the two animal models of the murine B16 melanoma and the melanotic Greenes melanoma No. 179 in hamsters. In mice given L-[18F]FBPA and L-BPA, the concentrations of 10B in B16 estimated from 18F radioactivity were lower than those measured by inductively coupled plasma-atomic emission spectroscopy. Lower estimated values were dependent on the time after injection and on the loading dose of L-BPA. The estimated 10B concentrations for Greens melanomas were comparable to the measured values. Positron emission tomography (PET) using L-[18F]FBPA allowed Greenes melanomas to be clearly visualized. In conclusion, when L-[18F]FBPA is used as a probe for L-BPA in BNCT of malignant melanomas, the melanoma can be localized and the 10B concentrations in tissues can be assessed in vivo using 18F radioactivity by PET.

Pharmacokinetics of 10B-p-boronophenylalanine in tumours, skin and blood of melanoma patients: a study of boron neutron capture therapy for malignant melanoma.

To optimize the neutron dose for boron neutron capture therapy (BNCT), the boron-10 (10B) concentration kinetics of 10B-p-boronophenylalanine (BPA) were analysed in 22 melanoma patients with primary or metastatic melanomas who received BPA and subsequently underwent BNCT or surgery. The blood concentration in nine patients receiving 179.7+/-14.9 mg/kg BPA increased with time during intravenous infusion, peaked at the end of administration and decreased thereafter. The peak values at the end of administration were 9.4 2.6 microg 10B/g blood, and half-lives for the initial and second components of the blood clearance were 2.8 and 9.2 h, respectively. Skin concentrations in the 10 patients varied from case to case; however, skin-to-blood ratios were relatively constant at 1.31+/-0.22 during the 6 h after the end of administration. Boron concentrations in the tumours resected from the seven patients who were operated on decreased in parallel to the blood values, the tumour-to-blood ratio being relatively constant at 3.40+/-0.83. The present analytical data of BPA pharmacokinetics support our previous approach for optimizing the timing of irradiation and setting the neutron flux large enough for tumour eradication but still tolerable for normal skin.

The relative biological effectiveness of 10B-neutron capture therapy for early skin reaction in the hamster.

The relative biological effectiveness (RBE) of 10B-neutron capture therapy (BNCT) on skin was analyzed using hamsters. The Kyoto University Research Reactor, which has a very low contamination of gamma rays and fast neutrons, was used as a thermal neutron source. Boron-10-para-boronophenylalanine hydrochloride ([10B]BPA.HCl) was administered to the hamsters. The evolution and time course of early skin reactions were assessed. These reactions were compared with those produced by electron beams. The maximum safe skin doses (no more than moist desquamation) of BNCT and electron beams were established to be 11 and 21 Gy, respectively. The RBE at this single dose with BNCT was found to be 1.94, assuming that the RBE of the gamma rays was 1.0 and each component of BNCT (mixed radiations) was simply additive.

Advances in the Control of Human Cutaneous Primary and Metastatic Melanoma by Thermal Neutron Capture Therapy

Differing in principle from boron neutron capture therapy (NCT) of brain tumors using passive accumulation of 10B, since 1972 our ideal) has been to develop a new 10B delivery system actively targeting cancers by utilizing their enhanced specific metabolic activity. As a prototype, we have been working with melanoma using 10B1-p-boronophenylalanine (10B1-BPA), a 10B-dopaanalogue, melanogenesis-seeking melanin polymer substrate2).

Boron neutron capture therapy (BNCT) for malignant melanoma with special reference to absorbed doses to the normal skin and tumor

Twenty-two patients with malignant melanoma were treated with boron neutron capture therapy (BNCT) using10B-p-boronophenylalanine (BPA). The estimation of absorbed dose and optimization of treatment dose based on the pharmacokinetics of BPA in melanoma patients is described. The doses of γ-rays were measured using small TLDs of Mg2SiO4 (Tb) and thermal neutron fluence was measured using gold foil and wire. The total absorbed dose to the tissue from BNCT was obtained by summing the primary and capture γ-ray doses and the high LET radiation doses from10B(n,α)7Li and14N(n,p)14C reactions. The key point of the dose optimization is that the skin surrounding the tumour is always irradiated to 18 Gy−Eq, which is the maximum tolerable dose to the skin, regardless of the10B-concentration in the tumor. The neutron fluence was optimized as follows. (1) The10B concentration in the blood was measured 15−40 min after the start of neutron irradiation. (2) The10B-concentration in the skin was estimated by multiplying the blood10B value by a factor of 1.3. (3) The neutron fluence was calculated. Absorbed doses to the skin ranged from 15.7 to 37.1 Gy−Eq. Among the patients, 16 out of 22 patients exhibited tolerable skin damage. Although six patients showed skin damage that exceeded the tolerance level, three of them could be cured within a few months after BNCT and the remaining three developed severe skin damage requiring skin grafts. The absorbed doses to the tumor ranged from 15.7 to 68.5 Gy−Eq and the percentage of complete response was 73% (16/22). When BNCT is used in the treatment of malignant melanoma, based on the pharmacokinetics of BPA and radiobiological considerations, promising clinical results have been obtained, although many problems and issues remain to be solved.

Increased Selective 10B-Uptake by Malignant Melanoma Using Systemic Administration of 10B1-BPA·Fructose Complex

10B1-para-Boronophenylalanine(10B1-BPA) has selective affinity for malignant melanoma. In our first human case, we succeeded in obtaining complete regression of a metastatic subcutaneous melanoma lesion by neutron capture therapy (NCT) using distant perilesional injections of 10B1-BPA hydrochloride.

Selective Melanoma Thermal Neutron Capture Therapy for Lymph Node Metastases

The success of treatment of tumors with NCT lies primarily with the development of suitable vectors to optimally carry 10B to the tumor site, efficient methods of their administration, and effective neutron beam delivery.

Biodistribution of boron concentration on melanoma-bearing hamsters after administration of p-, m-, o-boronophenylalanine.

Although p‐boronophenylalanine (p‐BPA), a boronate analogue of tyrosine, has proven to be one of the most successful compounds for boron neutron capture therapy (BNCT) of malignant melanoma, the selective uptake mechanism of this compound into melanoma cells is not well understood. Therefore, the relationship between the structure of BPA and its specific affinity to melanoma cells appears worthy of investigation. In the present study, m‐ and o‐boronophenylalanine (m‐ and o‐BPA) were administered to melanoma‐bearing hamsters and their uptake was measured. The time courses (0.5, 2.0, 4.0 and 48.0 h) of boron concentrations in melanoma, normal skin, and blood were determined in male Syrian (golden) hamsters bearing Greenes melanomas following a single intraperitoneal injection of either p‐, m‐ or o‐BPA (100 mg/kg of BPA·fructose in 1.0 ml of saline). The boron concentrations in these tissues were measured by inductively coupled plasma‐atomic emission spectrometry (ICP‐AES). In melanoma, the order of boron uptake was p‐ >m‐>o‐BPA at all time points, and the boron concentrations obtained with p‐BPA and m‐BPA resembled each other in that they had a peak at 2 h after administration and decreased with time. The melanoma/skin boron concentration ratio of p‐BPA had a peak at 4 h after administration and the ratio ranged between 7/1 and 8/1. On the other hand, m‐BPA and o‐BPA had a peak at 2 h and their ratios ranged between 4/1 and 5/1. The difference in the accumulations of p‐BPA and m‐BPA could be due to a difference in the property of p‐BPA as a tyrosine analogue for melanin synthesis. The accumulation of m‐BPA into melanoma might indicate the baseline level of metabolism‐related amino acid transport. Our experimental findings indicate that this melanin synthesis, or the structural analogy between the boron compound and tyrosine as a precursor of melanin, is an important factor in the increased accumulation of p‐BPA in melanoma cells.

Complex Formation of Phenylboronic Acid Derivatives with Aldopentoses and Oligosaccharides

p-Boronophenylalanine (p-bpa) has been studied for use in neutron capture therapy for melanoma [1,2,3,4]. The solubility of p-bpa is only 1.6 g/L in water, which is too small for medical uses. It is desirable and necessary to find a method to increase the solubility of p-bpa at the pH value of blood (pH 7.4).